In Alzheimer's disease, it is known that the accumulation of senile plaque containing amyloid beta-protein (hereinafter referred collectively to as Aβ) as a main component and of neurofibrillary tangles containing hyperphosphorylated tau protein (hereinafter referred collectively to as tau) as a main component proceeds to the degree that it cannot be treated, when the people around the patient or the physician notice the specific clinical symptoms of the disease. In other words, if the current diagnosis of Alzheimer's disease is compared to that of cancer, it is detected only when it has reached the end stage.
Recently, it has been revealed that even in the case of the extremely early stage of very mild Alzheimer's disease that corresponds to mild cognitive impairment (MCI), which is considered as partly precursor state of Alzheimer's disease, autopsy samples show the accumulation of many Aβ and tau, and the state is pathologically almost Alzheimer's disease. Therefore, in Alzheimer's disease, the histopathology is manifested far before the symptom of memory loss appears. In other words, there is a quite large difference between the histopathology and clinical picture of Alzheimer's disease (so-called difference between pathological Alzheimer's disease and clinical Alzheimer's disease).
As illustrated in FIG. 1, the accumulation of Aβ is considered to start 10 or more years earlier than that of tau in the brain of Alzheimer's disease. As is apparent from FIG. 1, since the tracing of Aβ was considered most appropriate in order to diagnose Alzheimer's disease in the extremely early stage or before its' development, almost all PET probes for the diagnosis of Alzheimer's disease were so-called probes for amyloid imaging to trace Aβ from the 20th to 21st century. At first, [11C] labeled probes were mainly used, but afterwards, the development of [18F] labeled probes that have a long half-life and are easily used in the clinical setting has been attempted. FIG. 2 illustrates the examples of probes for amyloid imaging that have been developed until now.
In the beginning of 2002, images showing administration of PET probes for amyloid imaging to Alzheimer's disease patients were introduced for the first time in the world (refer to Non-Patent Document 1). The team of Barrio et al., UCLA got the honor of this, and the probes used were [18F] FDDNP. Afterwards, however, [1C] PIB developed by General Electric, University of Pittsburgh, which has probably now been used for more than 1,000 clinical cases, became the mainstream of probes for amyloid imaging (refer to Non-Patent Document 2).
Many researchers assumed that amyloid imaging in the diagnosis of Alzheimer's disease would be a so-called versatile diagnostic method that enables the diagnosis of the disease with high sensitivity and specificity, as well as early diagnosis, differential diagnosis, diagnosis of severity (or progress), and preclinical diagnosis (so-called detection of presymptomatic high-risk individuals).
However, as clinical research progresses, issues were appearing gradually in the amyloid imaging, which was considered as versatile diagnostic method. These issues are explained by taking [11C] PIB as an example, as follows:
First, diagnosis of severity (or progress) is impossible. In other words, 2 years after a patient was diagnosed as Alzheimer's disease by [11C] PIB, there was no change in the accumulation of the probe regardless of the progress of the clinical symptoms (refer to Non-Patent Document 3). The reason is considered that the accumulation of Aβ to which [11C] PIB binds reaches a plateau far before MCI is seen prior to development of Alzheimer's disease. Therefore, the severity or progress of Alzheimer's disease cannot be diagnosed with [11C] PIB.
Second, there is a problem that considerable false positives are seen. Surprisingly, the ADNI (Alzheimer's Disease Imaging Initiative) held ahead of the International Conference on Alzheimer's Disease in Chicago in July 2008 reported that 53% of healthy elderly were [11C] PIB positive (refer to Non-Patent Document 4). Although the incidence rate of Alzheimer's disease is considered to be 4 to 6% of the population of 65 or more years old, the ADNI reported that 53% of the elderly except for Alzheimer's disease patients were [11C] PIB positive. Although the present inventors think the figure of 53% is an overestimate, the developers of [11C] PIB themselves recognize the possibility of considerable false positives (refer to Non-Patent Document 5).
The reason for these many false positives is believed to be that there is a considerable dispersion in the accumulation of Aβ in all of normal healthy subjects, MCI, and Alzheimer's disease.
Furthermore, in June to July 2008, it was successively reported that the effects of therapeutic drug (vaccines and secretase inhibitors) groups, which were expected to provide basic remedies based on the Alzheimer's disease/amyloid (or Aβ) hypothesis, were far below expectation. The most shocking was the report by Holmes et al. in Lancet that Aβ vaccines cannot stop the progress of the clinical symptoms at all although Aβ was removed from the brain of Alzheimer's disease patients (refer to Non-Patent Document 6).
However, another important information was provided in the report in Lancet; all accumulation of tau in the patients in Lancent progressed to the final stage. FIG. 3 illustrates the Braak stage of accumulation of Aβ and tau in Alzheimer's disease. For the Braak stage of post-mortem Case 7 and 8 of the report in Lancet, Aβ was considered not to be accumulated (or stage A), while the degree of tau accumulation was stage VI. This implies that in both cases the accumulation of Aβ was mild or less, while the accumulation of tau was the highest level of stage VI.
There were several reports that the histopathology correlated with the clinical symptoms of Alzheimer's disease was tau rather than Aβ in the early 1990s (Non-Patent Document 7). This was unexpectedly reaffirmed by the report by Holmes et al.
These findings strongly suggest that Aβ vaccines were less effective as therapeutic drugs after development of Alzheimer's disease and that the degree of Aβ accumulation does not always reflect the severity of Alzheimer's disease, as well as that it is more reasonable to trace tau rather than Aβ to diagnose the severity of Alzheimer's disease.
The present inventors think that by considering the clinical outcomes of vaccines, other therapeutic drugs, and probes for amyloid imaging, the relationship between amyloid (or Aβ) and tau in Alzheimer's disease should be revised to FIG. 4. As illustrated in FIG. 4, when there is low accumulation of amyloid, MCI and Alzheimer's disease develop when the tau accumulation reaches the threshold, and when the accumulation of amyloid is very high, MCI and Alzheimer's disease do not develop when the tau accumulation does not reach the threshold. That is to say, the amount of amyloid accumulation is not related to development of MCI and Alzheimer's disease, while tau accumulation defines this development. It is proposed to say “amyloid (or Aβ) has no threshold, but tau has one”.
As described above, tau imaging is probably superior to amyloid imaging, in order to diagnose the severity (or progress) of Alzheimer's disease, or to detect presymptomatic high-risk individuals for Alzheimer's disease correctly.
The present inventors think that it is probable that “tau imaging will play the leading role in diagnosis of Alzheimer's disease, supplemented by amyloid imaging in the future”.
The document in the relevant technical field includes, for example, (i) Okamura et al., J. Neurosci., 25 (4&), 10857-10862 (2005), (ii) EP 1574500 A1, (iii) Siemens US 2010/0239496 A1, and (iv) Korea KR 2010-0112423 A.